SUMMARY/ABSTRACT Pregnancy represents a unique challenge for the maternal-fetal immune interface, requiring the balance between immunosuppression, essential for the maintenance of semi-allogeneic fetus and pro-inflammatory host defense to protect the mother and fetus from invading organisms. Adaptation to repeated inflammatory stimuli may be critical in preventing rejection of the fetus by the exaggerated maternal inflammatory responses to mild/moderate infections that are common during human pregnancy. Immune tolerance/adaptation is a well-described phenomenon in which cells exposed to repeated pathogens become less responsive to subsequent exposures. This adaptation suppresses an overly aggressive inflammatory response to repeated infections that can be detrimental to the tissues rather than protective. Dampened immune response to repeated infections has been associated with protection against tissue injury and mortality in several human diseases. However, to date, the role of immune tolerance to repeated infections in the context of human pregnancy, and the exact mechanisms that contribute to the establishment of such immune adaptation to prevent inflammation-induced pathologic pregnancies are not explored. There is now extensive evidence that miRNAs play an important role in the maintenance of a healthy pregnancy, with a wide range of miRNAs implicated in endometrial receptivity, implantation, gestational tissues function, and labor. Our preliminary results indicate that repeated LPS (gram negative bacterial toxins) or LTA (gram-positive bacterial toxins) exposures to human placenta attenuates exaggerated inflammatory responses known to contribute to inflammation-associated pathologic pregnancies. Our data also point to the involvement of a human- and placenta-specific miRNA called miRNA-519c-3p (miR-519c) in the development of placental immune tolerance. Our overriding hypothesis is that repeated exposure of the placenta to pathogens induces a tolerant phenotype mediated by the miR-519c to guard the maternal-fetal interface from the exaggerated inflammation associated with pathologic pregnancies. We hypothesize that LPS/LTA induce placental trophoblasts to secrete miR-519c packaged within placental extracellular vesicles for delivery to nearby or distant cells. The miR-519c within the EVs will mediate down-regulation of exaggerated pro-inflammatory responses associated with repeated bacterial toxin exposures. We propose the following specific aims: Aim 1: Investigate the role of miR-519c in mediating immune adaptation in the human placenta after repeated infections and Aim 2: Investigate the molecular mechanisms of placental miR-519c mediating immune adaptation. These studies will set the stage for future experiments to test if decreased expression of miR-519c is linked to inflammation-associated pathologic pregnancies. This unique human- and placenta-specific miR-519c can be an excellent biomarker candidate as well as a therapeutic target for inflammatory diseases of pregnancy.